Differential UDP-galactose-4'-epimerase (GALE) enzymatic activity and mRNA expression in the rat mammary gland during lactation.

We have investigated the UDP-galactose-4'-epimerase (GALE) enzymatic activity and mRNA expression in the rat mammary gland during lactation. We report a dramatic increase in the GALE enzymatic activity correlated with an increase in the mRNA transcript expression. These results indicate a transcriptional regulation of the enzyme during lactation in the rat mammary gland. Our data are of double interest for further investigation: first, the mammary gland provides a suitable model for the characterisation of the transcriptional regulation elements of GALE which are still unknown in mammals; second, GALE expression could help to compensate UDP-galactose deficiency in classic galactosaemia.

Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group.

BACKGROUND: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease. OBJECTIVE: To determine the contribution of familial factors to the clinical expression of MS. METHODS: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features). RESULTS: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03). CONCLUSION: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

A systematic study of oligodendrocyte growth factors as candidates for genetic susceptibility to MS. French Multiple Sclerosis Genetics Group.

OBJECTIVE: To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis. BACKGROUND: Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS. METHODS: Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA. RESULTS: Negative results were obtained for all candidate genes. The lower limits of the relative risk (Xs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFbeta3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA. CONCLUSIONS: Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFbeta3, the only gene highlighted by this study, deserves further analysis.

Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach. French Multiple Sclerosis Genetics Group.

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

Chromosome 17q22-q24 and multiple sclerosis genetic susceptibility. American-French Multiple Sclerosis Genetic Group.

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.